rs745480657

Positions:

chr17-8115607-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_021628.3(ALOXE3):c.434G>A(p.Arg145His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ALOXE3
NM_021628.3 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.70

Variant links:

Genes affected

ALOXE3 (HGNC:13743): (arachidonate lipoxygenase 3) This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ALOXE3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-8115607-C-T is Pathogenic according to our data. Variant chr17-8115607-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOXE3	NM_021628.3 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant, splice_region_variant	4/16	ENST00000448843.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOXE3	ENST00000448843.7 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant, splice_region_variant	4/16	1	NM_021628.3	P1	Q9BYJ1-1
ALOXE3	ENST00000380149.6 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant, splice_region_variant	3/15	1		P1	Q9BYJ1-1
ALOXE3	ENST00000318227.4 linkuse as main transcript	c.434G>A	p.Arg145His	missense_variant, splice_region_variant	4/16	2		P1	Q9BYJ1-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251466

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1459852

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726384

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2021	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 4 and introduces a premature termination codon (PMID: 19131948). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 39550). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 19131948, 21668430, 32978145; Invitae). This variant is present in population databases (rs745480657, ExAC 0.009%). This sequence change replaces arginine with histidine at codon 145 of the ALOXE3 protein (p.Arg145His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Alters the last nucleotide of an exon and is predicted to damage the splice donor site; in vitro functional analysis in a mini gene assay showed that p.(Arg145His) leads to skipping of the following exon and a frameshift, denoted as p.Arg119GlyfsX12 (Eckl et al., 2009); This variant is associated with the following publications: (PMID: 34426522, 31589614, 32978145, 19131948, 21668430) -

Autosomal recessive congenital ichthyosis 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;T;.

Eigen

Benign

0.054

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.72

T;T;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

.;L;.

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.092

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.12

.;B;.

Vest4

0.42

MutPred

0.61

.;Loss of MoRF binding (P = 0.016);.;

MVP

0.90

MPC

0.96

ClinPred

0.35

GERP RS

4.5

Varity_R

0.074

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.77

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over